Various methods are used to identify polypeptides having desired activities such as therapeutic effects, the ability to produce useful compositions from feed stocks, etc. Directed evolution and other protein engineering technologies can be used to discover or enhance the activity of polypeptides of commercial interest. For example, if the activity of a known enzyme is insufficient for a commercial process, directed evolution may be used to improve the enzyme's activity on a substrate of interest. Current methods are often limited by the time and cost required to identify useful polypeptides. In some instances, it may take months or years, at great expense, to find a new polypeptide with the desired activity, if one is ever found. Part of the problem arises from the great number of polypeptide variants that must be screened. Thus, there is a need for improved methods and libraries that identify novel polypeptide variants having a desired activity.